P.1.c.048 Nitric oxide modulate methylphenidate-induced disruption on prepulse inhibition of the acoustic startle in swiss mice

P.1.c Basic and clinical neuroscience – Neuropharmacology P.1.c.048 Nitric oxide modulate methylphenidateinduced disruption on prepulse inhibition of the acoustic startle in swiss mice A.C. Issy1 ° , C. Salum1 , E.A. Del Bel1 . 1 University of S˜ao Paulo, Physiology – MEF – FORP, Ribeir˜ao Preto, Brazil Prepulse inhibition (PPI) of the acoustic startle refers to a decrease in the magnitude of startle response that is observed when the loud noise is preceded by a weak acoustic stimulus (a “prepulse”) [1]. Disruption of PPI involves deficient capacity to “gate” or inhibit attention to incoming sensory information and occurs in certain disorders in humans such as schizophrenia, or can be induced by dopamine (DA) releasers and agonists [2]. It has been suggested that Nitric Oxide (NO) interferes with DA transmission. The aim of this study was to investigate the contribution of NO to PPI analyzing the interaction between methylphenidate (DA releaser) and the NO synthase (NOS) inhibitors – NG nitro L-arginine (LNOARG), 7-Nitroindazole (7NI) or the soluble guanylate cyclase inhibitor – ODQ. Swiss mice (30−35g) received two i.p injections. The first injection, given one hour before testing, was of either saline (10 ml/kg) or LNOARG (10, 40 or 90 mg/kg) or 7NI (10, 30 or 60 mg/kg) or ODQ (5 or 10 mg/kg). The second injection, given 30 min before test, was either methylphenidate (30 or 60 mg/kg, ip) or saline. In another experiment mice received i.p injections of haloperidol (1 mg/kg), clozapine (1 or 5 mg/kg) or saline, one hour before testing, followed by methylphenidate (30 mg/kg, i.p., 30 min before testing) or saline. The PPI test consist of 64 trials randomly divided into pulse (P, white noise, 105dB), prepulse (pure tone; 7kHz; 80, 85 or 90dB), prepulse+pulse (PP) and no-stimuli – %PPI=[100(PP/P)*100]. The percentage of PPI was analyzed with repeated measures (MANOVA) with the treatment as the independent factor and the prepulse intensity as repeated measure. Duncan’s post hoc test (p < 0.05) was used to specify differences revealed by significant MANOVAS. Methylphenidate (30 and 60 mg/kg) induced significant PPI disruption (prepulse 80 and 85dB). NOS inhibitors and ODQ did not affect PPI but, when in combination with methylphenidate (30 mg/kg), LNOARG [40 mg/kg; F(11,98) = 4.33; P = 0.001], 7NI [10 mg/kg; F(7,87) = 5.66; p = 0.001] and ODQ [10 mg/kg; F(5,50) = 2.32; p = 0.056] attenuated the methylphenidate-induced disruption of PPI (MANOVA, post hoc Duncan, p < 0.05). The typical antipsychotic haloperidol reverted the disruption caused by methylphenidate, although the atypical antipsychotic clozapine did not (one-way ANOVA, Duncan’s test, p < 0.05). Our results corroborate the hypothesis that NO may not be a critical component of the intrinsic sensorimotor gating but it can modulate the DA effect on PPI given that the NOS inhibitors and ODQ markedly attenuated methylphenidate-induced disruption of PPI in a dosedependent manner. The influence of NO on methylphenidate effect possibly will occur through cGMP pathway. The effect of haloperidol on methylphenidate-induced disruption suggests that in Swiss mice D2 dopaminergic receptors have a prominent role on the modulation of sensorimotor system. Given that pharmacological prevention of PPI disruption may predict antipsychotic activity, our results stimulate the study of NOS inhibitors as potential therapeutical drugs. References [1] Hoffman H.S., Ison J.R., 1980, Reflex modulation in the domain of startle: Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev, 87:175–189.

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[2] Geyer M.A., Krebs-Thomson K., Braff D.L., Swerdlow N.R., 2001, Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology, 156: 117–154

P.1.c.049 Alertness and electrocortical activity after (co-)administration of MDMA and THC in healthy volunteers M.M. Lansbergen1 ° , G.J.H. Dumont1 , J.K. Buitelaar1 , J.M.A. van Gerven2 , R.J. Verkes1 . 1 Radboud University Nijmegen Medical Centre, Unit for Clinical Psychopharmacology and Neuropsychiatry (UCPN) Department of Psychiatry, Nijmegen, The Netherlands; 2 Centre for Human Drug Research (CHDR), Leiden, The Netherlands Background: Ecstasy/MDMA is often used in combination with other substances of abuse, especially cannabis (main active compound: THC). MDMA, an amphetamine, is a stimulant, whereas THC is generally considered as a sedative agent. Consequently, the separate usage of ecstasy and cannabis may have different effects on arousal and neural activity as compared to their combined usage. For example, the intake of MDMA leads to alertness as well as to decreased theta and alpha activity and increased beta activity. In contrast, the intake of cannabis results in relaxation and decreased theta, increased alpha, and decreased beta activity (2, 3, 4). The aim of the present study is to examine the separate drug effects as well as the interaction effects of acute MDMA and THC intake on alertness and resting state electrocortical activity. Methods: In a double blind, placebo controlled, crossover design, 11 healthy volunteers (18−27 years) attended four experimental sessions – placebo, MDMA (100 mg oral), THC (inhalation of three doses: 1×4 mg, 2×6 mg, interval of 1.5 hours), or MDMA plus THC. In each session, before and after drug administration, the Bond and Lader (Visual Analogue) Mood Rating Scale (BLMRS) was filled in to assess ‘alertness’, and electroencephalography (EEG) was recorded to obtain estimates of absolute theta (3.5−7 Hz, Fz), alpha (8−12 Hz, Pz), and beta activity (12.5−25 Hz, Cz). Separate repeated-measures analyses of variance were conducted for alertness and EEG activity (postminus pre-drug administration), using MDMA (active vs. placebo) and THC (active vs. placebo) as within-subjects factors. Results: A single dose of THC decreased feelings of alertness compared to placebo, F(1,9) = 14.06, p = 0.005. The coadministration of MDMA reduced this effect, although the intake of MDMA alone did not increase alertness as compared to placebo. No differences were found for alpha activity. A marginally significant MDMA × THC interaction effect, F(1,10) = 4.00, p = 0.073, was found for frontal theta activity. Whereas theta activity increased over time in the placebo condition, it decreased after drug administration with the greatest reduction after the combined intake of MDMA and THC. Regarding beta activity, main effects of MDMA, F(1,10) = 11.92, p = 0.006, and THC, F(1,10) = 10.21, p = 0.010, indicated that beta activity decreased significantly after the intake of MDMA and THC, but increased over time in the placebo condition. Conclusions: The findings indicate that THC substantially reduced alertness and that this effect was counteracted by the intake of MDMA. Whereas co-administration of MDMA and THC did not decrease beta activity significantly more than MDMA or THC administration alone, theta activity decreased to a greater extent after their combined usage. Decreased theta activity may be associated with increased autonomic responses to MDMA